Delirium in the critically ill: time to awaken?


Delirium is an acute dysfunctional state of the brain, typically seen among critically ill patients. The characteristic clinical feature of delirium is a disturbance in attention that evolves rapidly, associated with cognitive impairment, and unrelated to the underlying disease process. Impaired memory and disorientation, with the impediment of speech and perception are also common features. Critical illness-associated delirium adds to the disease burden and often leads to deleterious outcomes. Although a relatively common manifestation of multiorgan dysfunction in the critically ill, it is generally unmonitored, unnoticed, and an often-neglected aspect of care.1 Cognitive dysfunction may also be accepted by clinicians as the inevitable effect of sedative medication.2  

Delirium and clinical outcomes

The incidence of delirium ranges between 20–80% and is related to the severity of the underlying illness.3 Among hospitalized patients, delirium is an independent predictor of mortality. Furthermore, it increases the duration of hospital stay, with a higher likelihood of rehospitalization, long-term cognitive impairment, and adds to the cost of care.4

A prospective cohort study of 275 mechanically ventilated patients evaluated the impact of delirium on clinical outcomes.5 Fifty-one patients remained comatose and died in hospital. Among the 224 survivors, 183 (81.7%) experienced delirium during their ICU stay. The 6-month mortality was significantly higher among patients who developed delirium compared to those who did not (34% vs 15%, P =.03). Delirium was also associated with a significantly longer duration of hospital stay and an independent predictor of 6-month mortality on adjusted analysis. The incidence of cognitive impairment was higher at hospital discharge in patients who experienced delirium.  

Delirium assessment tools 

Screening for delirium and early identification is the key to timely and effective management. The Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption (PADIS) guidelines of the Society of Critical Care Medicine (SCCM) recommend delirium assessment in every nursing shift and more often as necessary using a reliable tool.6 The CAM-ICU evaluates patients in four domains, including acute change or fluctuation of mental status, inattention, altered conscious level, and disorganized thinking.3 The CAM-ICU assessment is rapid and relatively easy to perform at the bedside; however, it may not be feasible in patients with cognitive deficits, and those who are deeply sedated. Besides, it requires adaptation to the local language and culture. 

The Intensive Care Delirium Screening Checklist (ICDSC) includes eight dichotomized items, each carrying one point. Delirium is identified by a score of 4 or more on this checklist.7  

Types of delirium 

Delirium may present with hyperactive features, characterized by restlessness, agitated behavior and emotional lability. Hallucinations and illusions are also common. The aggressive nature of the disorder may interfere with the effective delivery of care. More difficult to diagnose, and hence, less often recognized, is the hypoactive type of delirium. Patients who experience hypoactive delirium are confused, withdrawn, and apathetic. Hypoactive delirium may also be characterized by slowing down of motor activity, lethargy, and drowsiness. A validated screening tool is crucial to screen for hypoactive delirium; it may otherwise be misinterpreted as fatigue or depression. Clinical outcomes from hypoactive delirium tend to be worse compared to the hyperactive type, with higher 6-month mortality.3 Mixed delirium is the most common type, with clinical manifestations fluctuating between the hypo and hyperactive types. 

The third type of delirium is sedation-related and rapidly reversible with a spontaneous awakening trial. Rapidly reversible, sedation-related delirium has been shown to be more benign and associated with fewer days on mechanical ventilation and in the hospital compared to delirium that persisted after cessation of sedation. This study also emphasizes the importance of daily sedation hold and assessment if feasible, among patients on mechanical ventilation.9

Pharmacological interventions for delirium 

Several classes of medication have been evaluated in the management of delirium among critically ill patients. Most of the available evidence suggests that such therapy is largely ineffective at preventing delirium. 

The HOPE-ICU trial evaluated the efficacy of haloperidol in reducing delirium among critically ill patients.10 Haloperidol 2.5 mg intravenously thrice daily was compared to placebo among patients who were mechanically ventilated and within 72 hours of admission to a mixed medical-surgical ICU. Haloperidol was discontinued after a 2-day delirium-free period, until discharge from ICU, or up to 14 days, whichever occurred earliest. In this study, the median number of days alive, not in a coma and free of delirium were comparable between patients who received haloperidol compared to the control group (5 vs. 6 days p = 0·53). Among the secondary outcomes, the 28-day mortality, the duration of mechanical ventilation, and the length of stay in ICU and hospital also did not differ significantly between the two groups. 

The multicentric REDUCE study included critically ill patients, with a predicted ICU stay of at least two days which was considered to be a risk factor for delirium.11 This RCT was conducted across 21 centers in the Netherlands. The initial design was a three-armed RCT that compared haloperidol 1 or 2 mg 8 hourly intravenously with placebo. The 1 mg dose was ceased early for futility upon the recommendation of the data and safety board. The 28-day survival, the primary outcome, was not significantly different between the haloperidol 2 mg and the placebo groups (83.3% vs. 82.7%). The incidence of delirium, the number of delirium-free and coma-free days, the duration of mechanical ventilation, and length of stay in the ICU and in hospital were also similar between the two groups. 

In the MIND-USA trial, haloperidol and ziprasidone (an atypical antipsychotic drug) were compared to placebo in a three-armed trial among patients with acute respiratory failure or shock who experienced hypoactive or hyperactive delirium.12 The maximum dose of haloperidol was 40 mg and ziprasidone 20 mg daily, intravenously. The CAM-ICU severity scale was used to evaluate the presence of delirium. In this study, delirium occurred in 48% of patients studied; the majority of patients experienced hypoactive delirium (89%). The median number of  days alive and coma- and delirium-free were similar between patients in all three groups. Survival at 30 and 90 days, the duration of mechanical ventilation, ICU, and hospital stay were also similar between all three groups of patients. 

Burry et al. evaluated the impact of pharmacotherapy on the duration of delirium in critically ill patients.13 In their systematic review they analyzed 11 studies, including 1153 patients. Multiple agents were used for delirium control, including antipsychotics, dexmedetomidine, statins, morphine, ondansetron, and the anticholinesterase inhibitor, rivastigmine. No drug, compared to placebo, reduced the number of delirium-free days or days in coma. Besides, the use of physical restraints, duration of ICU stay, cognitive outcomes, and mortality were not significantly different. Among all the agents evaluated, dexmedetomidine alone was found to shorten the duration of delirium in an RCT that included 74 patients from Australia and New Zealand. In this study, dexmedetomidine use was associated with earlier extubation and more rapid resolution of delirium. However, a large number of patients were excluded at initial screening (around 21,000 patients were screened) and hence, lacks external validity.14

The non-pharmacological approach

Several risk factors contribute to the occurrence of delirium in critically ill patients. Interventions directed toward mitigating these risk factors have been shown to reduce the incidence of delirium. These include reorientating patients to time and place, providing clocks to help them keep in touch with the time, spectacles and hearing aids that are used regularly15, and early mobilization. Interventions may be minimized during sleep time, including blood draws, and routine examinations that could be performed later. The patient is best addressed by their name, and information may be offered regarding the disease process in a simplified manner with positive reinforcement. Other measures that may reduce the incidence of delirium include minimization of noise levels, effective management of pain, and keeping track of drugs that may be implicated in delirium.16,17

A prospective observational study evaluated the efficacy of non-pharmacologic interventions bundled with nursing education and multidisciplinary intervention including intensivists, clinical pharmacists, and critical care nursing staff.18 A sedation algorithm and mobilization protocol were combined with delirium screening performed 4-hourly using the ICDSC tool. This protocolized approach was compared with a pre-protocol phase as the control group. The adoption of the protocolized approach resulted in a significant reduction in the incidence and the duration of delirium. After controlling for risk factors including age, the APACHE II score, mechanical ventilation, and the presence of dementia, the odds of developing delirium reduced by 57% with the protocolized approach compared to the pre-protocol phase. 

A “bundled” strategy 

The PADIS guidelines recommend a multicomponent approach. The ABCDEF bundle includes Assessment, prevention, and management of pain (A), Both spontaneous awakening and spontaneous breathing trials (B), Choice of analgesics and sedatives (C), Monitoring and management of delirium (D), Early mobilization and exercise (E), and engagement with family (F).  Barnes-Daly et al. conducted a prospective cohort study using this bundle as part of a quality improvement initiative among patients admitted to a mixed medical-surgical ICU. Higher compliance with the bundled approach was independently associated with hospital survival on adjusted analysis. Besides, complete compliance with the bundle was associated with more days alive and free of delirium and coma.19

Balas et al. evaluated the efficacy and safety of a similar bundled approach. In this before-after study, implementation of the bundle resulted in more ventilator-free days and a lower incidence of delirium. Besides, patients were mobilized more often during ICU stay compared to the control group.20

Key points 

  • Although delirium is associated with adverse clinical outcomes including increased mortality, it is an oft-neglected aspect of care among critically ill patients
  • The incidence of delirium is closely related to the severity of the underlying illness and may occur in 20–80% of ICU patients 
  • Delirium is difficult to detect in the absence of a concerted approach including the use of screening tools, and often remains undiagnosed. The CAM-ICU and the ICDSC are sensitive screening tools that enable early detection of delirium  
  • The diagnosis of the hypoactive type of delirium is more likely to be missed and carries worse clinical outcomes compared to the hyperactive type
  • No pharmacological agent has been shown to be effective in the prevention of delirium; however, pharmacotherapy may be required if the presence of delirium interferes with the delivery of care 
  • A largely non-pharmacological, bundled approach is the most effective strategy in delirium management. This includes provision of adequate pain relief, avoidance of excessive sedation, and early mobilization. Patients must be given spectacles and hearing aids that they are used to, reorientated, and allowed to interact with the family as much as possible. Positive reinforcement about their progress is also an important facet of care.  


1.         Morandi A, Piva S, Ely EW, et al. Worldwide Survey of the “Assessing Pain, Both Spontaneous Awakening and Breathing Trials, Choice of Drugs, Delirium Monitoring/Management, Early Exercise/Mobility, and Family Empowerment” (ABCDEF) Bundle. Crit Care Med. 2017;45(11):e1111-e1122. doi:10.1097/CCM.0000000000002640

2.         Girard TD, Thompson JL, Pandharipande PP, et al. Clinical phenotypes of delirium during critical illness and severity of subsequent long-term cognitive impairment: a prospective cohort study. Lancet Respir Med. 2018;6(3):213-222. doi:10.1016/S2213-2600(18)30062-6

3.         Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA. 2001;286(21):2703-2710. doi:10.1001/jama.286.21.2703

4.         Stollings JL, Kotfis K, Chanques G, Pun BT, Pandharipande PP, Ely EW. Delirium in critical illness: clinical manifestations, outcomes, and management. Intensive Care Med. 2021;47(10):1089-1103. doi:10.1007/s00134-021-06503-1

5.         Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004;291(14):1753-1762. doi:10.1001/jama.291.14.1753

6.         Devlin JW, Skrobik Y, Gélinas C, et al. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Critical Care Medicine. 2018;46(9):e825. doi:10.1097/CCM.0000000000003299

7.         Bergeron N, Dubois MJ, Dumont M, Dial S, Skrobik Y. Intensive Care Delirium Screening Checklist: evaluation of a new screening tool. Intensive Care Med. 2001;27(5):859-864. doi:10.1007/s001340100909

8.         Robinson TN, Raeburn CD, Tran ZV, Brenner LA, Moss M. THE MOTOR SUBTYPES OF POST-OPERATIVE DELIRIUM IN THE ELDERLY. Arch Surg. 2011;146(3):295-300. doi:10.1001/archsurg.2011.14

9.         Patel SB, Poston JT, Pohlman A, Hall JB, Kress JP. Rapidly reversible, sedation-related delirium versus persistent delirium in the intensive care unit. Am J Respir Crit Care Med. 2014;189(6):658-665. doi:10.1164/rccm.201310-1815OC

10.       Page VJ, Ely EW, Gates S, et al. Effect of intravenous haloperidol on the duration of delirium and coma in critically ill patients (Hope-ICU): a randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2013;1(7):515-523. doi:10.1016/S2213-2600(13)70166-8

11.       van den Boogaard M, Slooter AJC, Brüggemann RJM, et al. Effect of Haloperidol on Survival Among Critically Ill Adults With a High Risk of Delirium. JAMA. 2018;319(7):680-691. doi:10.1001/jama.2018.0160

12.       Girard TD, Exline MC, Carson SS, et al. Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness. N Engl J Med. 2018;379(26):2506-2516. doi:10.1056/NEJMoa1808217

13.       Burry L, Hutton B, Williamson DR, et al. Pharmacological interventions for the treatment of delirium in critically ill adults. Cochrane Emergency and Critical Care Group, ed. Cochrane Database of Systematic Reviews. Published online September 3, 2019. doi:10.1002/14651858.CD011749.pub2

14.       Reade MC, Eastwood GM, Bellomo R, et al. Effect of Dexmedetomidine Added to Standard Care on Ventilator-Free Time in Patients With Agitated Delirium: A Randomized Clinical Trial. JAMA. 2016;315(14):1460-1468. doi:10.1001/jama.2016.2707

15.       McCusker J, Cole MG, Voyer P, et al. Environmental factors predict the severity of delirium symptoms in long-term care residents with and without delirium. J Am Geriatr Soc. 2013;61(4):502-511. doi:10.1111/jgs.12164

16.       Balas MC, Rice M, Chaperon C, Smith H, Disbot M, Fuchs B. Management of delirium in critically ill older adults. Crit Care Nurse. 2012;32(4):15-26. doi:10.4037/ccn2012480

17.       Popeo DM. Delirium in older adults. Mt Sinai J Med. 2011;78(4):571-582. doi:10.1002/msj.20267

18.       Rivosecchi RM, Kane-Gill SL, Svec S, Campbell S, Smithburger PL. The implementation of a nonpharmacologic protocol to prevent intensive care delirium. J Crit Care. 2016;31(1):206-211. doi:10.1016/j.jcrc.2015.09.031

19.       Barnes-Daly MA, Phillips G, Ely EW. Improving Hospital Survival and Reducing Brain Dysfunction at Seven California Community Hospitals: Implementing PAD Guidelines Via the ABCDEF Bundle in 6,064 Patients. Crit Care Med. 2017;45(2):171-178. doi:10.1097/CCM.0000000000002149

20.       Balas MC, Vasilevskis EE, Olsen KM, et al. Effectiveness and Safety of the Awakening and Breathing Coordination, Delirium Monitoring/Management, and Early Exercise/Mobility Bundle*: Critical Care Medicine. 2014;42(5):1024-1036. doi:10.1097/CCM.0000000000000129

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